Abstract
SummaryCancer cachexia, the unintentional loss of lean body mass, is associated with decreased quality of life and poor patient survival. Hypogonadism, involving a reduction in circulating testosterone, is associated with the cachectic condition. At this time there is a very limited understanding of the role of hypogonadism in cancer cachexia progression. This gap in our knowledge is related to a lack of functional hypogonadal models associated with cancer cachexia. The ApcMin/+ mouse is an established colorectal cancer model that develops an IL-6 dependent cachexia which is physiologically related to human disease due to the gradual progression of tumor development and cachexia. The purpose of this study was to assess the utility of the ApcMin/+ mouse for the examination of hypogonadism during cancer cachexia and to investigate if IL-6 has a role in this process. We report that ApcMin/+ mice that are weight stable have comparable testosterone levels and gonad size compared to wild type mice. Cachectic ApcMin/+ mice exhibit a reduction in circulating testosterone and gonad size, which has a significant association with the degree of muscle mass and functional strength loss. Circulating testosterone levels were also significantly associated with the suppression of myofibrillar protein synthesis. Skeletal muscle and testes androgen receptor expression were decreased with severe cachexia. Although testes STAT3 phosphorylation increased with severe cachexia, systemic IL-6 over-expression for 2 weeks was not sufficient to reduce either testes weight or circulating testosterone. Inhibition of systemic IL-6 signaling by an IL-6 receptor antibody to ApcMin/+ mice that had already initiated weight loss was sufficient to attenuate a reduction in testes size and circulating testosterone. In summary, the ApcMin/+ mouse becomes hypogonadal with the progression of cachexia severity and elevated circulating IL-6 levels may have a role in the development of hypogonadism during cancer cachexia.
Highlights
Cancer induced cachexia is a condition of unintentional body weight loss associated with the loss of skeletal muscle with or without the loss in adipose tissue (Tisdale, 2010)
The purpose of this study was to assess the utility of the ApcMin/+ mouse for the examination of hypogonadism during cancer cachexia and to investigate if IL-6 has a role in this process
We report that ApcMin/+ mice that are weight stable have comparable testosterone levels and gonad size compared to wild type mice
Summary
Cancer induced cachexia is a condition of unintentional body weight loss associated with the loss of skeletal muscle with or without the loss in adipose tissue (Tisdale, 2010). The complex nature of cachexia is associated with systemic disorders that include chronic inflammation, insulin resistance, anemia, anorexia and hypogonadism (Evans et al, 2008). While some of these systemic disorders associated with wasting, such as chronic inflammation and insulin resistance, have been and are being widely investigated (Argiles et al, 2009; Carson and Baltgalvis, 2010; Fearon et al, 2012), there remain gaps in our understanding of hypogonadism’s regulatory role in the progression of cancer cachexia. A barrier in our understanding of testosterone action during cancer cachexia has been directly associated with tumor implant models that induce create a rapid and severe cachexia, but do not allow for the physiological examination of the hypogonadal state (Murphy et al, 2012)
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